Use of sulfonamides

ABSTRACT

The present invention is concerned with compounds of formula I ##STR1## wherein Z, R 1  and R 2  are as defined herein, as well as their pharmaceutically acceptable salts as therapeutically active substances against central nervous system disorders and for the production of corresponding medicaments.

This is a divisional of application Ser. No. 08/869,063 filed on Jun. 4,1997 U.S. Pat. No. 5,939,451.

SUMMARY OF THE INVENTION

The invention is concerned with compounds of formula ##STR2##

wherein

Z is a substituted phenyl, substituted pyridyl, substituted pyrimidyl orsubstituted indolyl group of formula a-e ##STR3## R¹ is hydrogen, amino,lower alkylamino, lower dialkylamino, lower alkyl, halogen ortrifluoromethyl;

R² is hydrogen or lower alkyl;

R³ is hydrogen, amino, lower alkylamino, lower dialkylamino, loweralkyl, CF₃, lower alkoxy or halogen;

R⁴ is amino, lower alkylamino, lower dialkylamino, lower alkyl, loweralkoxy or halogen;

R⁵ is hydrogen, lower alkyl, lower alkylamino, di-lower alkylamino,lower alkoxy or halogen;

R⁶ is lower alkylamino, di-lower alkylamino, lower alkoxy, halogen orCF₃ ;

R⁷ is amino, lower alkylamino, di-lower alkylamino, lower alkoxy, loweralkylsulfanyl, mercapto, pyrrolidin-1-yl or azetidin-1-yl;

R⁸ is amino, lower alkylamino, di-lower alkylamino, benzylamino, loweralkoxy, lower alkylsulfanyl, halogen, pyrrolidin-1-yl or azetidin-1-yl;

R⁹ and R¹⁰ each independently are lower alkoxy or lower alkylamino;

R¹¹ is hydrogen or halogen;

R¹² is hydrogen or lower alkyl, and

a is an optional double bond,

with the proviso that R⁷ and R⁸ do not simultaneously signify methoxy,

as well as their pharmaceutically acceptable salts, and theiradministration to a host in need for use as therapeutically activesubstances.

It has been found that the compounds of formula I, as well as theirpharmaceutically acceptable salts, surprisingly possess a selectiveaffinity to 5HT-6 receptors. They are accordingly useful for thetreatment or prevention of Alzheimer's Disease. They are also useful forthe treatment or prevention of central nervous disorders such as, forexample, psychoses, schizophrenia, manic depressions (Bryan L. Roth etal., J. Pharmacol. Exp. Ther., 268, pages 1403-1410 (1994)), depressions(David R. Sibley et al., Mol. Pharmacol., 43, pages 320-327 (1993)),neurological disorders (Anne Bourson et al., J. Pharmacol. Exp. Ther.,274, pages 173-180 (1995); R. P.Ward et al., Neuroscience, 64, pages1105-1110 (1995)), memory disorders, Parkinson's disease, amyotrophiclateral sclerosis and Huntington's disease (Andrew J. Sleight et al.,Neurotransmissions, 11, pages 1-5 (1995)).

An object of the present invention is the use of compounds of formula Iand of their pharmaceutically usable salts for the treatment orprevention of illnesses of the aforementioned kind and, respectively,for the production of corresponding medicaments, the compounds offormulas Ia₁, Ia₂, Ib₁, Ib₂, Ic₁, IC₂, Id₁, Id₂ and Ie or theirpharmaceutically usable salt per se or for use as therapeutically activesubstances, the manufacture of the compounds of formulas Ia₁, Ia₂, Ib₁,Ib₂, Ic₁, Ic₂, Id_(a), Id₂ and Ie, medicaments containing a compound offormula I or pharmaceutically usable salt thereof as well as theproduction of such medicaments.

DETAILED DESCRIPTION OF THE INVENTION

Known compounds of formula I in which Z is a substituted phenyl residueare described for example by R. Behnisch et al. in Chemische Berichte,81, No. 4, pages 297-306, (1947), for example compounds with halogensubstituents on the phenyl residue such as4-amino-N-(3,5-dichlorophenyl)-benzenesulfonamide or4-amino-(3,5-dibromo-phenyl)-benzenesulfonamide, or compounds withmethyl or methoxy substituents on the phenyl residue such as4-amino-N-(3,5-dimethyl-phenyl)-benzenesulfonamide or4-amino-N-(3,5-dimethoxy-phenyl)-benzenesulfonamide. The sulfonamidesdescribed here have an activity against malaria.

J. L. Frederick et al. in Journal of Org. Chem., 26, pages 4715-4716,(1961) describe fluorosulfanilanilides such as, for example, thecompound 4-amino-N-(3,5-difluoro-phenyl)-benzenesulfonamide, as well astheir production and use as antibacterial agents.

Further, J. K. Seydel in Mol. Pharmacol., 2, pages 259-265, (1966)describes the in vitro activity of a series of sulfonamides against Ecoli.

Bergeim et al. in Journal of the American Chem. Soc., 69, pages 583-587,(1947) describe the production of some amino-sulfanilanisides such as,for example, the compound4-amino-N-(3-methoxy-phenyl)-benzenesulfonamide as possible antimalarialagents.

Not one of the publications enumerated above mentions thatphenyl-benzenesulfonamides could also suitable as active compounds forthe treatment of neurological disorders.

Known compounds of formula I in which Z is a substituted pyridineresidue are described, for example, by R. Urban et al. in HelvetiaChimica Acta, 47, pages 363-377, (1964), for example the compounds4-amino-N-(4,6-dimethoxy-pyridin-2-yl)-benzenesulfonamide,4-amino-N-(2-methoxy-6-bromo-pyridin-3-yl)-benzenesulfonamide,4-amino-N-(2-methoxy-6-methyl-pyridin-4-yl)-benzenesulfonamide or4-amino-N-(2,6-dimethoxy-pyridin-4-yl)-benzenesulfonamide. Theproduction of aminomethoxypyridines and sulfanilamides is described,together with their antibacterial properties. Also in this publicationno mention is to be found with respect to a potential activity againstneurological disorders.

Known compounds of formula I in which Z is a substituted pyrimidineresidue are described for example by Bretschneider et al. in Monatsheftefur Chemie, 92, pages 183-192, (1961). The production of2,6-disubstituted 4-sulfanilamidopyrimidines, for example of thecompound4-amino-N-(2,6-diethylsulfanyl-pyrimidin-4-yl)-benzenesulfonamide, isdescribed. In Monatshefte fur Chemie, 95, pages 207-213, (1964)Bretschneider et al. describe further syntheses of6-sulfanilamido-2,4-dimethoxypyrimidine.

W. Baker et al. in Journal of the American Chem. Soc., 69, pages3072-3078, (1947) describe the production of substitutedsulfanilamidopyrimidines, such as, for example, the compound4-amino-N-(4,6-dimethoxy-pyrimidin-2-yl)-benzenesulfonamide, as well astheir potential use as antibacterial agents.

Sulfanil derivatives of 2,6-di-substituted pyrimidines, such as, forexample, the compound4-amino-N-(2,6-bis-dimethylamino-pyrimidin-4-yl)-benzenesulfonamide, aredescribed in French Patent Application FR 1 383 287.

Not one of these publications mentions that sulfonamides which carry apyrimidine residue could also be suitable as an active compounds for thetreatment of neurological disorders.

The use of compounds which carry a primary amino group for the treatmentof neurological disorders is quite generally described in InternationalPatent Application WO 92/14456. A large number of different groups ofcompound, such as, for example, p-aminobenzoic acids,p-aminophenylacetic acids, aminonicotinic acid, 2,3-diamino-propionicacid and the like are named. In this enumeration of different groups ofcompound there are also named, inter alia, sulfanilamides and 1-aminosubstituted derivatives of sulfanilamides (p--H₂ N--C₆ H₄ --SO₂ NHR).The compound 4-amino-N-(2,6-dimethoxy-pyrimidin-4-yl)-benzenesulfonamidespecifically referred to by name is excluded by means of a disclaimerfrom the use of the compounds of formula I for the treatment orprevention of disorders of the aforementioned kind.

The compounds of formula I embrace the following groups:

a) anilides of formula Ia ##STR4## wherein R¹, R², R³ and R⁴ have thesignificances given in formula I;

b) compounds of formula Ib ##STR5## wherein R¹, R², R⁵ and R⁶ have thesignificances given in formula I;

c) compounds of formulae Ic and Id ##STR6## wherein R¹, R², R⁷, R⁸, R⁹and R¹⁰ have the significances given in formula I;

and

d) compounds of formula Ie ##STR7## wherein R¹, R², R¹¹, R¹² and a havethe significances given in formula I.

The following compounds of formulae Ia, Ib, Ic, Id and Ie are especiallypreferred for a use of the aforementioned kind:

4-Amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide;

4-amino-N-(6-ethylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide;

4-amino-N-(2-dimethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide;

4-amino-N-(2-dimethylamino-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamide;

4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-N-methyl-benzenesulfonamide;

4-amino-N-(2-azetidin-1-yl-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide;

4-amino-N-(2-azetidin-1-yl-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamide;

4-amino-N-(6-methylamino-2-pyrrolidin-1-yl-pyrimidin-4-yl)-benzenesulfonamide;

4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide;

4-amino-N-(2,6-bis-methylamino-pyridin-4-yl)-benzenesulfonamide;

4-amino-N-(2-ethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamide;

4-amino-N-(2-dimethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamide;

4-amino-N-(2,6-bis-ethylamino-pyridin-4-yl)-benzenesulfonamide;

N-(2,6-bis-methylamino-pyrimidin-4-yl)-3-chloro-benzenesulfonamide;

N-(2,6-bis-methylamino-pyrimidin-4-yl)-3-trifluoromethyl-benzenesulfonamide;

4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide;

4-amino-N-(3,5-dimethoxy-phenyl)-benzenesulfonamide;

4-amino-N-(3,5-dichloro-phenyl)-benzenesulfonamide;

4-amino-N-(3,5-dibromo-phenyl)-benzenesulfonamide and

4-amino-N-(1H-indol-4-yl)-benzenesulfonamide.

The term "lower alkyl" used in the present description denotes residuesof 1 to 7, preferably of 1 to 4, carbon atoms, such as, for example,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.

The term "lower alkoxy" denotes a lower alkyl residue in the sense ofthe foregoing definition bonded via an oxygen atom, such as, forexample, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy andt-butoxy.

The term "lower alkylamino" denotes a lower alkyl residue in the senseof the foregoing definition bonded via a NH group, such as, for example,methylamino and ethylamino.

The term "lower dialkylamino or di-lower alkylamino" denotes two similaror different lower alkyl residues in the sense of the foregoingdefinition bonded via a nitrogen atom, such as, for example,dimethylamino, diethylamino or methyl-ethyl-amino.

The term "lower alkylsulfanyl" denotes a lower alkyl residue in thesense of the foregoing definition bonded via a sulfur atom, such as, forexample, methylsulfanyl (--S--CH₃) and ethylsulfanyl (--S--CH₂ CH₃).

The term "halogen" embraces fluorine, chlorine, bromine and iodine.

With respect to formula Ia, the following known compounds are preferredor especially preferred for use as therapeutically active substances:

4-Amino-N-(3,5-dimethoxy-phenyl)-benzenesulfonamide,

4-amino-N-(3,5-dichloro-phenyl)-benzenesulfonamide,

4-amino-N-(3,5-dibromo-phenyl)-benzenesulfonamide,

4-amino-N-(3,5-dimethyl-phenyl)-benzenesulfonamide and

4-amino-N-(3-methoxy-phenyl)-benzenesulfonamide.

In one aspect, the invention relates to compounds of formulas Ia₁ andIa₂ ##STR8##

wherein

R^(1a) signifies 3-trifluoromethyl, 3-halo or 4-halo;

R^(3a) signifies hydrogen, halogen, lower alkoxy, amino or loweralkylamino;

R^(4a) signifies amino or lower alkylamino and

R¹³ signifies lower alkyl;

with the proviso that R^(3a) is different from hydrogen when R^(4a)signifies amino, as well as their pharmaceutically acceptable salts.

Preferred compounds of formula Ia₁ in which

R^(3a) signifies hydrogen, amino or methylamino and

R^(4a) signifies amino or methylamino

and their manufacture are described in Examples 34-36.

Example 37 describes the manufacture of a compound of formula Ia₂ inwhich R^(1a) signifies 3-trifluoromethyl and R¹³ signifies methyl.

With respect to formula Ib, the following known compounds are preferredfor use as therapeutically active substances:

4-Amino-N-(2,6-dimethoxy-pyridin-4-yl)-benzenesulfonamide and

4-amino-N-(2-methoxy-6-methyl-pyridin-4-yl)-benzenesulfonamide.

In one aspect, the invention relates to compounds of formulas Ib₁ andIb₂ ##STR9##

wherein

R^(1b) signifies 4-halo, 3-halo or 3-trifluoromethyl;

R^(5a) signifies hydrogen, lower alkyl, lower alkylamino, di-loweralkylamino or halogen;

R^(6a) signifies CF₃, lower alkylamino, di-lower alkylamino or halogenand

R¹⁴ signifies lower alkyl;

with the proviso that R^(5a) is different from hydrogen when R^(6a)signifies halogen, as well as their pharmaceutically acceptable salts.

Preferred are compounds of formula Ib₁ in which

R^(5a) signifies hydrogen, methyl, methylamino, ethylamino,dimethylamino, chlorine or bromine and

R^(6a) signifies methylamino, ethylamino, dimethylamino, CF₃ or bromine,

with the proviso that R^(5a) is different from hydrogen when R^(6a)signifies bromine, and their manufacture are described in Examples38-47, 51 and 53.

Preferred compounds of formula Ib₂ in which

R^(1b) signifies 4-chloro, 3-chloro or 3-trifluoromethyl and

R¹⁴ signifies methyl,

and their manufacture are described in Examples 48-50.

In one aspect, the invention relates to compounds of formulas Ic₁ andIC₂ ##STR10##

wherein

R^(1c) signifies hydrogen, 4-halo, 4-lower alkyl, 3-halo or3-trifluoromethyl;

R² signifies hydrogen or lower alkyl;

R^(7a) signifies amino, lower alkylamino, di-lower alkylamino, mercapto,pyrrolidin-1-yl or azetidin-1-yl;

R^(8a) signifies amino, lower alkylamino, di-lower alkylamino,benzylamino, lower alkoxy, pyrrolidin-1-yl or azetidin-1-yl and

R¹⁵ signifies lower alkyl;

with the proviso that R^(8a) is different from lower alkoxy and fromdi-lower alkylamino when R^(7a) signifies di-lower alkylamino, as wellas their pharmaceutically acceptable salts.

In one aspect, the invention relates to compounds of formula Ic₁ inwhich

R² signifies hydrogen or methyl;

R^(7a) signifies amino, methylamino, ethylamino, propylamino,isopropylamino, dimethylamino, mercapto, pyrrolidin-1-yl orazetidin-1-yl and

R^(8a) signifies amino, methylamino, ethylamino, propylamino,isopropylamino, dimethylamino, benzylamino, methoxy, pyrrolidin-1-yl orazetidin-1-yl,

with the proviso that R^(8a) is different from dimethylamino and methoxywhen R^(7a) signifies dimethylamino, and their manufacture are describedin Examples 1-25.

In one aspect, the invention relates to compounds of formula Ic₂ inwhich

R^(1c) signifies hydrogen, 4-fluoro, 4-chloro, 4-methyl, 4-tert.butyl,3-chloro or 3-trifluoromethyl and

R¹⁵ signifies methyl,

and their manufacture are described in Examples 27-33.

In one aspect, the invention relates to compounds of formulas Id₁ andId₂ ##STR11##

wherein

R^(1d) signifies 3-trifluoromethyl, 4-trifluoromethyl, 3-halo or 4-haloand

R^(9a) and R^(10a) signify lower alkylamino,

as well as their pharmaceutically acceptable salts.

Example 26 describes the manufacture of a compound of formula Id₁ inwhich R^(9a) and R^(10a) signify methylamino.

In one aspect, the invention relates to compounds of formula Ie##STR12## wherein R¹, R², R¹¹, R¹² and a have the significance given inclaim 1.

The manufacture of compounds of formula Ie in which R¹ is amino and R¹¹is hydrogen is described in Example 52.

The compounds of formula I and their salts, insofar as they are oneaspect of the invention and their manufacture has not already beendescribed, can be manufactured in a known manner from a compound offormula II ##STR13##

wherein

R^(1s) has the significance given for R¹ or signifies protected aminoand

X signifies halogen or --NHY in which Y stands for an alkali metal, forexample sodium or potassium,

by reacting a compound of formula II in which X signifies halogen:

a) with a compound of the formula ##STR14##

wherein

R^(3s) signifies hydrogen, lower alkoxy, halogen, protected amino orprotected lower alkylamino and

R^(4a) signifies protected amino or protected lower alkylamino,

and cleaving of the amino protecting groups; or

b) with a compound of the formula ##STR15##

wherein

R^(5s) signifies halogen and

R^(6s) signifies halogen, lower alkyl or CF₃,

and, if desired, reacting the reaction product with a lower alkylamineor di-lower alkylamine and cleaving off the amino protecting group; or

c) with a compound of the formula ##STR16##

wherein

R^(7s) signifies mercapto and

R^(8s) signifies amino, lower alkylamino, di-lower alkylamino,benzylamino, lower alkoxy, pyrrolidin-1-yl or azetidin-1-yl,

and, if necessary, cleaving off the amino protecting group; or

d) reacting a compound of formula II in which X signifies --NHY firstlywith a compound of the formula ##STR17##

wherein

R^(7s) signifies amino, lower alkylamino, mercapto, pyrrolidin-1-yl orazetidin-1-yl and

R^(8s) signifies halogen,

and then, if desired, treating the reaction product with a loweralkylamine, di-lower alkylamine, azetidine, pyrrolidine or analcoholate; or

e) reacting a compound of formula II in which X signifies halogen with acompound of the formula ##STR18##

wherein

R^(11s) signifies hydrogen or halogen and R¹² signifies hydrogen orlower alkyl,

and, if desired, reducing to a compound of formula Ie in which a doesnot signify a double bond; or

f) reacting a compound of the formula ##STR19##

wherein

R^(9s) and R^(10s) signify lower alkoxy,

with a lower alkylamine; or

g) reacting a sulfadimethoxine of the formula ##STR20##

wherein

R^(7s) and R^(8s) signify lower alkoxy,

with a lower alkylamine; and

h) if desired, converting a compound of formula I into apharmaceutically acceptable salt.

All process variants referred to herein can be carried out in a knownmanner.

For the manufacture of compounds of formula Ia, the starting materialsof formulae II and IIIa are conveniently reacted at room temperature ina suitable solvent, for example pyridine.

For the alkylation of the amino group, the protected amino group can bereacted, for example, with a lower alkyl iodide.

The acetyl group is a suitable amino protecting group.

The cleavage of the amino protecting group is effected by the additionof a base (e.g. NaOH) by heating under reflux.

In the case of compounds of formula Ia the protecting group cleavage isalways the last reaction step.

For the manufacture of compounds of formula Ib, the starting materialsof formula II (X=halogen) and IIIb are conveniently reacted at 20-80°C., preferably at 60° C., in a suitable solvent, for example pyridine.

For the manufacture of compounds of formula Ic, the starting materialsof formula II (X=halogen) are reacted with compounds of formula IIIc.

The cleavage of the amino protecting group is effected by base treatmentas described above.

The reaction product of the reaction of a compound of formula II with acompound of formula IIIb, for example4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide, can be used forthe manufacture of compounds of formula Ib in which R⁵ signifieshalogen, lower alkylamino or di-lower alkylamino and R⁶ represents loweralkylamino or di-lower alkylamino by reaction with a lower alkylamine ordi-lower alkylamine at 60-200° C.

For the manufacture of compounds of formula I in which R² signifieslower alkyl, a corresponding sulfonamide can be reacted withdiazomethane in a known manner (Example 19).

The starting materials required for the manufacture of the compounds offormula I are known compounds or can be prepared in analogy to knownprocesses. These reactions will be familiar to any person skilled in theart.

The binding of the compounds of formula I in accordance with theinvention to 5-HT₆ receptors was determined as follows.

Membranes obtained from HEK 293 cells which had been transfected with5-HT₆ receptors from rats were used.

The cells were purified by two-fold centrifugation (10 minutes at 3000g) in phosphate-buffered sodium chloride solution. The cell mass wassuspended in an ice-cold solution consisting of 50 mM Tris-HCl buffer,10 mM MgCl₂, 0.5 mM EDTA and 0.1 mM phenylmethylsulfonyl fluoride andhomogenized (Polytron homogenizer, 15 seconds at maximum velocity). Thehomogenizate was incubated at 37° C. for 10 minutes and subsequentlycentrifuged (20 minutes at 20000 g). The cell mass was again suspendedin the aforementioned Tris buffer solution. The resulting cellconcentration was 4×10⁷ cells/ml. Aliquots each comprising 1 ml of thehomogenizate were freeze-dried at (-80)° C.

Displacement tests were carried out in order to determine the affinityof the test substance to the 5-HT₆ receptor. In order to carry out thetest, the homogenizate was thawed and suspended in a buffer solution (pH7.4) consisting of 50 mM Tris-HCl buffer, 5 mM MgCl₂, 10⁻⁵ M pargylineand 0.1% ascorbic acid. 100 μl of membrane suspension, 50 μl of [³H]-LSD (specific activity 85 Ci/Mmol, final concentration 1 nM) and 50μl of test substance solution were incubated at 37° C. for 1 hour. Therespective substance was investigated at 7 different concentrations from10 ⁻¹⁰ M to 10⁻⁴ M. The binding reaction of the test substance wasinterrupted by rapid filtration through [a] Whatman GF/B filter. Thefilter was washed with 2×2 ml of Tris-HCl buffer (50 mM, pH 7.4) and theradioactivity on the filter was measured by scintillation spectroscopyin 2 ml of scintillation solution. All tests were carried out intriplicate and were repeated three times.

The pKi values (pKi=-log₁₀ Ki) of the test substances have beendetermined. The Ki value is defined by the following formula: ##EQU1##with the IC₅₀ values being those concentrations of test compounds in nMby which 50% of the ligands bonded to the receptor are displaced. [L] isthe concentration of ligand and the KD value is the dissociationconstant of the ligand.

The compounds in accordance with the invention have a selective affinityto 5-HT 6 receptors with a Ki value below 1.6 μM and pKi values between6.00 and 8.00.

The compounds of formula I and the pharmaceutically acceptable salts ofthe compounds of formula I can be used as medicaments, for example inthe form of pharmaceutical preparations. The pharmaceutical preparationscan be administered orally, for example in the form of tablets, coatedtablets, dragees, hard and soft gelatine capsules, solutions, emulsionsor suspensions.

The administration can, however, also be effected rectally, for examplein the form of suppositories, parenterally, for example in the form ofinjection solutions. The compounds of formula I can be processed withpharmaceutically inert, inorganic or organic carriers for the productionof pharmaceutical preparations. Lactose, corn starch or derivativesthereof, talc, stearic acids or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragees and hardgelatine capsules. Suitable carriers for soft gelatine capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like. Depending on the nature of the active substance no carriersare, however, usually required in the case of soft gelatine capsules.Suitable carriers for the production of solutions and syrups are, forexample, water, polyols, glycerol, vegetable oil and the like. Suitablecarriers for suppositories are, for example, natural or hardened oils,waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceuticallyacceptable salt thereof and a therapeutically inert carrier are also anobject of the present invention, as is a process for their production,which comprises by bringing one or more compounds of formula I and/orpharmaceutically acceptable acid addition salts and, if desired, one ormore other therapeutically valuable substances into a galenicaladministration form together with one or more therapeutically inertcarriers.

In accordance with the invention compounds of formula I as well as theirpharmaceutically acceptable salts are useful for treating or preventingAlzheimer's Disease. The compounds of formula I and theirpharmaceutically acceptable salts are also useful in the treatment orprevention of central nervous disorders such as depressions, psychoses,schizophrenia, neurological disorders, memory disorders, Parkinson'sdisease, amoytrophic lateral sclerosis and Huntington's disease and forthe production of corresponding medicaments. The dosage can vary withinwide limits and will, of course, be fitted to the individualrequirements in each particular case. In the case of oral administrationthe dosage lies in range of about 0.01 mg per dose to about 1000 mg perday of a compound of general formula I or the corresponding amount of apharmaceutically acceptable salt thereof, although the upper limit canalso be exceeded when this is found to be indicated.

The following Examples illustrate the present invention in more detail.However, they are not intended to limit its scope in any manner.

EXAMPLE 1

4-Amino-N-(2-amino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide

0.98 g (0.006 mol) of 2-amino-4,6-dichloropyrimidine and 3.03 g (0.012mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirred in10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, thesolvent was distilled off in a high vacuum, the residue was partitionedin ethyl acetate/water, the inorganic phase was saturated with sodiumchloride and the remaining ethyl acetate dissolved in the aqueous wasdistilled off on a rotary evaporator. The aqueous phase was made acidwith 1N HCl, the crystals which separated were filtered off undersection and washed with water. After drying there were obtained 1.37 g(67%) ofN-[4-(2-amino-6-chloro-pyrimidin-4-yisulfamoyl)-phenyl]-acetamide asbeige crystals; m.p.: 272-273° C. (dec.).

0.885 g (0.0026 mol) ofN-[4-(2-amino-6-chloropyrimidin-4-ylsulfamoyl)phenyl]-acetamide wasdissolved in 31 ml of 0.5N NaOH and boiled at reflux for 3 hours. Themixture was extracted with ethyl acetate, the aqueous phase wassaturated with sodium chloride and the remaining ethyl acetate wasdistilled off on a rotary evaporator. Then, the aqueous phase was madeacid with 3N HCl and the precipitate which separated was filtered offunder suction. After drying there was obtained 0.76 g (86%) of4-amino-N-(2-amino-6-chloro-pyrimidine-4-yl)-benzenesulfonamide as beigecrystals; m.p.: >265° C. (dec.).

0.527 g (0.00176 mol) of4-amino-N-2-amino-6-chloropyrimidin-4-yl)benzenesulfonamide wasdissolved in 22 ml (0.176 mol) of 8M methylamine in ethanol and stirredin an autoclave at 130° C. for 16 hours. The suspension obtained wasfiltered, the precipitate was dissolved in ethanol and treated withactive charcoal, filtered and freed from the solvent. The residue wassuspended in ethanol and filtered. There was obtained 0.055 g (10%) of4-amino-N-(2-amino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide asbeige crystals; m.p.: 285° C. (dec.).

EXAMPLE 2

4-Amino-N-(2-amino-6-ethylamino-pyrimidin-4-yl)-benzenesufonamide

0.50 g (0.00167 mol) of4-amino-N-(2-amino-6-chloropyrimidin-4-yl)-benzenesufonamide and 11 ml(0.167 mol) of ethylamine were dissolved in 20 ml of ethanol and stirredin an autoclave at 130° C. for 4 hours. The reaction mixture was freedfrom solvent, the residue was suspended in 5 ml of ethanol and treatedin an ultrasound bath for 15 minutes. The precipitate was filtered off,dissolved 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted topH 6 with 0.1N HCl. The precipitate was filtered off under suction,washed with water and dried. There was obtained 0.271 g (53%) of4-amino-N-(2-amino-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamide asbeige crystals; m.p. 272-274° C.

EXAMPLE 3

4-Amino-N-(2-amino-6-benzylamino-pyrimidin-4-yl)-benzenesulfonamide

0.30 g (0.001 mol) of4-amino-N-(2-amino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide and 11 ml(0.1 mol) of benzylamine were dissolved in 15 ml of ethanol and stirredin an autoclave at 130° C. The reaction mixture was freed from solvent,the residue was suspended in 5 ml of ethanol and treated in anultrasound bath for 15 minutes. The precipitate was filtered off,dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjustedto pH 6 with 0.1N HCl. The precipitate was filtered off under suction,washed with water and dried. There was obtained 0.15 g (41%) of4-amino-N-(2-amino-6-benzylamino-pyrimidin-4-yl)-benzenesulfonamide asbeige crystals; m.p.; 221° C. (dec.).

EXAMPLE 4

4-Amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide

5.0 g (0.016 mol) of sulfadimethoxine were dissolved in 60 ml of 33 percent ethanolic methylamine and stirred in an autoclave at 150° C. for 30hours. The mixture was cooled, freed completely from solvent, trituratedin 70 ml of methanol for 2 hours. and suction filtered. There wereobtained 4.2 g (84%) of4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide asgrey crystals; m.p. 303-305° C.

11.5 g (0.0373 mol) of4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide weretreated with 11.5 ml of 25 percent aqueous hydrochloric acid and stirredat 0° C. for 1 hour. The water was evaporated completely and the residuewas recrystallized from ethanol/diethyl ether. There were obtained 11.8g (89%) of4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamidehydrochloride (1:1.8) as pale yellow crystals; m.p. 175-250° C. (dec.).

EXAMPLE 5

4-Amino-N-(6-ethylamino-2-methylamino-pyrimidin-4-yl)benzenesulfonamide

2.0 g (0.011 mol) of (4,6-dichlorpyrimidin-2-yl)-methylamine and 5.67 g(0.022 mol) N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirredin 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, thesolvent was distilled off in a high vacuum, the residue was partitionedin ethyl acetate/water, the inorganic phase was saturated with sodiumchloride and the residual ethyl acetate dissolved in the aqueous phasewas distilled off on a rotary evaporator. The aqueous phase was madeacid with 1N HCl, the crystals which separated were filtered off undersuction and washed with water. After drying there were obtained 2.72 g(68%) ofN-[4-(6-chloro-2-methylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamideas beige crystals. m.p.: >240° C. (dec.).

2.7 g (0.008 mol) ofN-[4-(6-chloro-2-methylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamidewere dissolved in 76 ml of 1N NaOH and boiled at reflux for 3 hours. Themixture was extracted with ethyl acetate, the aqueous phase wassaturated with sodium chloride and the residual ethyl acetate wasdistilled off on a rotary evaporator. Then, the aqueous phase was madeacid with 3N HCl and the precipitate which separated was filtered offunder suction. After drying there were obtained 2.12 g (89%) of4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamidehydrochloride (1:1.9) as white crystals; MS (ISN): me/e=312 (C₁₁ H₁₁ClN₅ O₂ S⁻).

0.314 g (0.001 mol) of4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and6.6 ml (0.1 mol) of ethylamine were stirred in 15 ml of ethanol in anautoclave at 130° C. for 3 hours. The reaction mixture was freed fromsolvent, the residue was suspended in 8 ml of ethanol and treated in anultra-sound bath for 15 minutes. The precipitate was filtered off,dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjustedto pH 6 with 01N HCl. The precipitate was filtered off under suction,washed with water and dried. There was obtained 0.18 g (56%) of4-amino-N-(6-ethylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamideas white crystals; m.p.: 252° C. (dec.).

EXAMPLE 6

4-Amino-N-(6-isopropylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide

0.314 g (0.001 mol) of4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and8.6 ml (0.1 mol) of isopropylamine were stirred in 15 ml of ethanol inan autoclave at 130° C. for 3 hours. The reaction mixture was freed fromsolvent, the residue was suspended in 8 ml of ethanol and treated in anultra sound bath for 15 minutes. The precipitate was filtered off,dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjustedto pH 6 with 0.1N HCl. The precipitate was filtered off under suction,washed with water and dried. There was obtained 0.12 g (36%) of4-amino-N-(6-isopropylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p. 240° C. (dec.).

EXAMPLE 7

4-Amino-N-(6-dimethylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide

0.314 g (0.001 mol) of4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and18 ml (0.1 mol) of dimethylamine in ethanol (5.6M) were stirred in anautoclave at 130° C. for 4 hours. The reaction mixture was freed fromsolvent, the residue was suspended in 5 ml of ethanol and treated in anultrasound bath for 15 min. The precipitate was filtered off, dissolvedin 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6with 0.1N HCl. The precipitate was filtered off under suction, washedwith water and dried. There was obtained 0.30 g (78%) of4-amino-N-(6-dimethylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p.: >300° C.

EXAMPLE 8

4-Amino-N-(6-azetidin-1-yl-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide

0.314 g (0.001 mol) of4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and1.0 ml (0.015 mol) of trimethyleneimine were stirred in 20 ml of ethanolin an autoclave at 130° C. for 4 hours. The reaction mixture was freedfrom solvent, the residue was suspended in 5 ml of ethanol and treatedin an ultrasound bath for 15 mins. The precipitate was filtered off,dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjustedto pH 6 with 0.1N HCl. The precipitate was filtered off under suction,washed with water and dried. There was obtained 0.24 g (72%) of4-amino-N-(6-azetidin-1-yl-2-methylamino-pyrimidin-4-yl)-benzenesulfonamideas white crystals; m.p.: 295-296° C.

EXAMPLE 9

4-Amino-N-(2-methylamino-6-pyrrolidin-1-yl-pyrimidin-4-yl)-benzenesulfonamide

0.314 g (0.001 mol) of4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and2.5 ml (0.15 mol) of pyrrolidine were stirred in 20 ml of ethanol in anautoclave at 130° C. for 4 hours. The reaction mixture was freed fromsolvent, the residue was suspended in 5 ml of ethanol and treated in anultrasound bath for 15 min. The precipitate was filtered off, dissolvedin 150 ml of 1N NaOH and filtered. The filtrate was adjusted to pH 6with 1N HCl. The precipitate was filtered off under suction, washed withwater and dried. There was obtained 0.22 g (63%) of ⁴-amino-N-(2-methylamino-6-pyrrolidin-1-yl-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p.: >300° C.

EXAMPLE 10

4-Amino-N-(2-ethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide

2.0 g (0.011 mol) of (4,6-dichloropyrimidin-2-yl)-ethylamine and 5.67 g(0.022 mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium salt werestirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then,the solvent was distilled off in a high vacuum, the residue waspartitioned in ethyl acetate/water, the inorganic phase was saturatedwith sodium chloride and the residual ethyl acetate dissolved in theaqueous phase was distilled off on a rotary evaporator. The aqueousphase was made acid with 1N HCl, the crystals which separated werefiltered off under suction and washed with water. After drying therewere obtained 2.88 g (75%) ofN-[4-(6-chloro-2-ethylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamideas beige crystals, which were used directly in the next step.

2.88 g (0.0075 mol) ofN-[4-(6-chloro-2-ethylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamidewere dissolved in 76 ml of 1N NaOH and boiled at reflux for 3 hours. Themixture was extracted with ethyl acetate, the aqueous phase wassaturated with sodium chloride and the residual ethyl acetate wasdistilled on a rotary evaporator. Then, the aqueous phase was made acidwith 3N HCl and the precipitate which separated was filtered off undersuction. After drying there were obtained 2.2 g (90%) of4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide aswhite crystals; m.p.: 172-173° C.

0.1 g (0.00031 mol) of4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide wasdissolved in 20 ml of ethanol and stirred with 0.6 ml (0.0043 mol) oftrimethylamine and 0.1 g (0.0015 mol) of methylamine hydrochloride in anautoclave at 130° C. for 4 hours. The reaction mixture was freed fromsolvent, the residue was suspended in 5 ml of ethanol and treated in anultrasound bath for 15 minutes. The precipitate was filtered off,dissolved in 150 ml of 1N NaOH and filtered. The filtrate was adjustedto pH 6 with 0.1N HCl. The precipitate was filtered off under suction,washed with water and dried. There was obtained 0.053 g (54%) of4-amino-N-(2-ethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p.: 261-263° C.

EXAMPLE 11

4-Amino-N-(2,6-bis-ethylamino-pyrimidin-4-yl)-benzenesulfonamide

1.50 g (0.00483 mol) of sulfadimethoxine were dissolved in 25 ml ofethanol, treated with 12.5 ml (0.193 mol) of cooled ethylamine andstirred in an autoclave at 180° C. for 24 hours. The mixture was cooledand freed completely from solvent. The residue was suspended in 150 mlof hot ethanol and filtered off under suction. There was obtained 0.79 g(40%) of4-amino-N-(2,6-bis-ethylamino-pyrimidin-4-yl)-benzenesulfonamide as palebeige crystals; m.p. 245-250° C.

0.79 g (0.00234 mol) of4-amino-N-(2,6-bis-ethylamino-pyrimidin-4-yl)-benzenesulfonamide wasdissolved in 150 ml of methanol, treated with 2.0 ml (0.0070 mol) of3.5N ethanolic hydrochloric acid and stirred at 0° C. for 2 hours. Thesolution was freed completely from solvent and the residue wasrecrystallized from ethanol/diethyl ether. There was obtained 0.61 g(70%) of4-amino-N-(2,6-bis-ethylamino-pyrimidin-4-yl)-benzenesulfonamidehydrochloride as pale beige crystals; m.p. 197-208° C.

EXAMPLE 12

4-Amino-N-(2-ethylamino-6-isopropylamino-pyrimidin-4-yl)-benzenesulfonamide

0.5 g (0.0015 mol) of4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide wasdissolved in 20 ml of ethanol and stirred with 13 ml (0.15 mol) ofisopropylamine in an autoclave at 130° C. for 4 hours. The reactionmixture was freed from solvent, the residue was suspended in 5 ml ofethanol and treated in an ultrasound bath for 15 minutes. Theprecipitate was filtered off, dissolved in 10 ml of 0.1N NaOH andfiltered. The filtrate was adjusted to pH 6 with 0.1N HCl. Theprecipitate was filtered off under suction, washed with water and dried.There was obtained 0.20 g (37%) of4-amino-N-(2-ethylamino-6-isopropylamino-pyrimidin-4-yl)-benzenesulfonamideas white crystals; m.p.: 258-259° C.

EXAMPLE 13

4-Amino-N-(6-dimethylamino-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide

0.5 g (0.0015 mol) of4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide wasdissolved in 20 ml of 33% dimethylamine in ethanol and stirred in anautoclave at 130° C. for 4 hours. The reaction mixture was freed fromsolvent, the residue was suspended in 5 ml of ethanol and treated in anultrasound bath for 15 minutes. The precipitate was filtered off,dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjustedto pH 6 with 0.1N HCl. The precipitate was filtered off under suction,washed with water and dried. There was obtained 0.426 g (83%) of4-amino-N-(6-dimethylamino-2-ethylamino-pyrimidin-4-ylbenzenesulfonamide as white crystals; m.p.: 301-302° C.

EXAMPLE 14

4-Amino-N-(6-azetidin-1-yl-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide

0.3 g (0.000915 mol) of4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide wasdissolved in 20 ml of ethanol, treated with 0.93 ml (0.0137 mol) oftrimethyleneimine and stirred in an autoclave at 130° C. for 4 hours.The reaction mixture was freed from solvent, the residue was suspendedin 5 ml of ethanol and treated in an ultrasound bath for 15 min. Theprecipitate was filtered off, dissolved in 10 ml of 0.1N NaOH andfiltered. The filtrate was adjusted to pH 6 with 0.1N HCl. Theprecipitate was filtered off under suction, washed with water and dried.There was obtained 0.248 g (78%) of4-amino-N-(6-azetidin-1-yl-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamideas white crystals; m.p.: 292-293° C.

EXAMPLE 15

4-Amino-N-(2,6-bis-propylamino-pyrimidin-4-yl)-benzenesulfonamide

1.50 g (0.00483 mol) of sulfadimethoxine were suspended in 20 ml ofethanol, treated with 16 ml (0.193 mol) of propylamine and stirred in anautoclave at 140° C. for 65 hours. The mixture was cooled and, after 24hours., the crystals which separated were filtered off under suction.There was obtained 0.75 g (50%) of4-amino-N-(2,6-bis-propylamino-pyrimidin-4-yl)-benzenesulfonamide aspale beige crystals; m.p. 211-215° C.

0.75 g (0.00205 mol) of4-amino-N-(2,6-bis-propylamino-pyrimidin-4-yl)-benzenesulfonamide wasdissolved in 100 ml of methanol, treated with 1.5 ml (0.0062 mol) of3.5N ethanolic hydrochloric acid and stirred at 0° C. for 2 hours. Thesolution was freed completely from solvent and the residue wasrecrystallized from ethanol/diethyl ether. There was obtained 0.86 g(82%) of4-amino-N-(2,6-bis-propylamino-pyrimidin-4-yl)-benzenesulfonamidehydrochloride as beige crystals; m.p. 189-195° C.

EXAMPLE 16

4-Amino-N-(6-ethylamino-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamide

2.42 g (0.0117 mol) of (4,6-dichloropyrimidin-2-yl)-ethylamine and 5.0 g(0.020 mol) N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirredin 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, thesolvent was distilled off in a high vacuum, the residue was partitionedin ethyl acetate/water, the inorganic phase was saturated with sodiumchloride and the residual ethyl acetate dissolved in the aqueous phasewas distilled off on a rotary evaporator. The aqueous phase was madeacid with 1N HCl, the precipitate which thereby separated was filteredoff under suction and washed with water. This was used directly withoutdrying in the next step.

The crude product obtained in the step described previously wasdissolved in 100 ml of 1N NaOH and boiled at reflux for 3 hours. Themixture was extracted with ethyl acetate, the aqueous phase wassaturated with sodium chloride and the residual ethyl acetate wasdistilled off on a rotary evaporator. Then, the aqueous phase was madeacid 3N HCl and the precipitate which thereby separated was filteredunder suction. After drying they were obtained 2.22 g (55% based on the(4,6-dichloropyrimidine-2-yl)-ethylamine used in the preceding step) of4-amino-N-(6-chloro-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamideas white crystals; m.p.: 94-95° C.

0.1 g (0.000293 mol) of4-amino-N-(6-chloro-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamidewas dissolved in 20 ml of ethanol, treated with 1.93 ml (0.0293 mol) ofethylamine and stirred in an autoclave at 130° C. for 4 hours. Thereaction mixture was freed from solvent, the residue was suspended in 5ml of ethanol and treated in an ultrasound bath for 15 min. Theprecipitate was filtered off, dissolved in 10 ml of 0.1N NaOH andfiltered. The filtrate was adjusted to pH 6 with 0.1N HCl. Theprecipitate was filtered off under suction, washed with water and dried.There was obtained 0.044 g (43%) of4-amino-N-(6-ethylamino-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamideas white crystals; m.p.: 266-267° C.

EXAMPLE 17

4-Amino-N-(2-dimethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide

0.50 g (0.00153 mol) of4-amino-N-(2-dimethylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamidewere dissolved in 20 ml (0.176 mol) of 8M methylamine in ethanol andstirred in an autoclave at 130° C. for 4 hours. The reaction mixture wasfreed from solvent and the residue was chromatographed on silica gelwith methanol/dichloromethane 1:19. There was obtained 0.10 g (21%) of4-amino-N-(2-dimethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p: 253-254° C.

EXAMPLE 18

4-Amino-N-(2-dimethylamino-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamide

0.2 g (0.00061 mol) of4-amino-N-(6-chloro-2-dimethylamino-pyrimidin-4-yl)-benzenesulfonamidewere dissolved in 20 ml of ethanol, treated with 4.2 ml (0.061 mol) ofethylamine and stirred in an autoclave at 130° C. for 4 hours. Thereaction mixture was freed from solvent, the residue was suspended in 5ml of ethanol and treated in an ultrasound bath for 15 minutes. Theprecipitate was filtered off, dissolved in 10 ml of 0.1N NaOH andfiltered. The filtrate was adjusted to pH 6 with 0.1N HCl. Theprecipitate was filtered off under suction, washed with water and dried.There was obtained 0.082 g (40%) of4-amino-N-(2-dimethylamino-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p.: 237-238° C.

EXAMPLE 19

4-Amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-N-methyl-benzenesulfonamide

0.65 g (0.0021 mol) of4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide wasdissolved in a mixture of 100 ml of methanol and 400 ml ofdimethylformamide and treated with 60 ml of a solution of diazomethanein diethyl ether. The mixture was stirred at room temperature for 30minutes. The solvent was distilled off and the residue waschromatographed over 50 g of SiO₂ with 5% of methanol in methylenechloride as the eluent. There was obtained 0.24 g (35%) of4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-N-methyl-benzenesulfonamideas a yellow solid; m.p.: 79-80° C.

EXAMPLE 20

4-Amino-N-(6-azetidin-1-yl-2-dimethylamino-pyrimidin-4-yl)-benzenesulfonamide

0.20 g (0.00061 mol) of4-amino-N-(6-chloro-2-dimethylamino-pyrimidin-4-yl)-benzenesulfonamidewas dissolved in 20 ml of ethanol, treated with 0.62 ml (0.0092 mol) oftrimethyleneimine and stirred in an autoclave at 130° C. for 4 hours.The reaction mixture was freed from solvent, the residue was suspendedin 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. Theprecipitate was filtered off, dissolved in 10 ml of 0.1N NaOH andfiltered. The filtrate was adjusted to pH 6 with 0.1N HCl. Theprecipitate was filtered off under suction, washed with water and dried.There was obtained 0.13 g (61%) of4-amino-N-(6-azetidin-1-yl-2-dimethylamino-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p.: 239-240° C.

EXAMPLE 21

4-Amino-N-(2-azetidin-1-yl-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide

2.0 ml (0.030 mol) of trimethyleneimine and 2.30 ml (0.020 mol) of2,4,6-trichloropyrimidine were stirred in 50 ml of ethanol at roomtemperature for 3 hours. The solvent was distilled off, the residue wassuspended in diethyl ether and washed with saturated NaHCO₃ solution.The organic phase was dried over MgSO₄, concentrated and the residue waschromatographed on silica gel with diethyl ether/hexane 1:5 to 2:1(gradient elution). The first fraction (Rf: 0.39, diethyl ether/hexane1:3) contained 0.67 g (16%) of 2-azetidin-1-yl-4,6-dichloro-pyrimidineas white crystals; m.p: 190° C. The second fraction contained 1.50 g(37%) of 2,4-dichloro-6-azetidin-1-ethyl-pyrimidine as white crystals;m.p.: 129-130° C.

0.65 g (0.0032 mol) of 2-azetidin-1-yl-4-6-dichloro-pyrimidine and 1.6 g(0.0064 mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium salt werestirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then,the solvent was distilled off in a high vacuum, the residue waspartitioned in ethyl acetate/water, the inorganic phase was saturatedwith sodium chloride and the residual ethyl acetate dissolved in theaqueous phase was distilled off on a rotary evaporator. The aqueousphase was made acid with 1N HCl and the precipitate which separated wasfiltered off under suction and washed with water. This was used directlywithout drying in the next step.

The crude product obtained in the step previously described wasdissolved in 50 ml of 1N NaOH and boiled at reflux for 2 hours. Themixture was extracted with ethyl acetate, the aqueous phase wassaturated with sodium chloride and the residual ethyl acetate wasdistilled off on a rotary evaporator. Then, the aqueous phase was madeacid with 3N HCl and the precipitate which thereby separated wasfiltered off under suction. After drying there was obtained 0.66 g (60%based on the 2-azetidin-1-yl-4,6-dichloro-pyrimidine used in thepreceding step) of4-amino-N-(2-azetidin-1-yl-6-chloro-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p.: >203° C. (dec.).

0.20 g (0.00059 mol) of4-amino-N-(2-azetidin-1-yl-6-chloro-pyrimidin-4-yl)-benzenesulfonamidewas dissolved in 20 ml of ethanol, treated with 0.4 g (0.00588 mol) ofmethylamine hydrochloride and 2.28 ml (0.0176 mol) of triethylamine andstirred in an autoclave at 130° C. for 8 hours. The reaction mixture wasfreed from solvent and the residue was chromatographed on silica gelwith methanol/dichloromethane 1:19. There was obtained 0.053 g (27%) of4-amino-N-(2-azetidin-1-.yl-6-methylamino-pyrimidin-4-yl)-benzenesulfonamideas light beige crystals; m.p.: >260° C. (dec.)

EXAMPLE 22

4-Amino-N-(2-azetidin-1-yl-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamide

0.2 g (0.00061 mol) of4-amino-N-(2-azetidin-1-yl-6-chloro-pyrimidin-4-yl)-benzenesulfonamidewas dissolved in 20 ml of ethanol, treated with 3.9 ml (0.061 mol) ofethylamine and stirred in an autoclave at 130° C. for 12 hours. Thereaction mixture was free from solvent, the residue was suspended in 5ml of ethanol and treated in an ultrasound bath for 15 minutes. Theprecipitate was filtered off, dissolved in 10 ml of 0.1N NaOH andfiltered. The filtrate was adjusted to pH 6 with 0.1N HCl. Theprecipitate was filtered off under suction, washed with water and dried.There was obtained 0.090 g (44%) of4-amino-N-(2-azetidin-1-yl-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p.: 260-262° C.

EXAMPLE 23

4-Amino-N-(6-methylamino-2-pyrrolidin-1-yl-pyrimidin-4-yl)-benzenesulfonamide

0.58 g (0.00266 mol) of 4,6-dichloro-2-pyrrolidin-1-yl-pyrimidine and1.36 g (0.00539 mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium saltwere stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours.Then, the solvent was distilled off in a high vacuum, the residue waspartitioned in ethyl acetate/water and extracted. The aqueous phase wasmade acid with 4N HCl and extracted with ethyl acetate. Both organicphases were combined and concentrated. The residue was recrystallizedfrom a small amount of ethanol and the mother liquor was chromatographedover silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. Therewas obtained a total of 0.62 g (66%) ofN-[4-(6-chloro-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamideas whitish crystals; m.p. 229-233° C.

0.62 g (0.00175 mol) ofN-[4-(6-chloro-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamidewas dissolved in 20 ml of ethanol, treated with 1.36 g (0.0201 mol) ofmethylamine hydrochloride and 5.3 ml (0.038 mol) of triethylamine andstirred in an autoclave at 140° C. for 17 hours. The mixture was freedcompletely from solvent, the residue was partitioned in ethylacetate/water and filtered off under suction. There was obtained 0.30 g(44%) ofN-[4-(6-methylamino-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamideas beige crystals; m.p. 271-274° C.

0.30 g (0.00077 mol) ofN-[4-(6-methylamino-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamidewas boiled at reflux in 30 ml of 1N aqueous sodium hydroxide for 3hours. The mixture was cooled and extracted with ethyl acetate. Crystalsthen separated from the aqueous phase and, after suction filtration,were chromatographed over silica gel with ethyl acetate/ethanol 9:1 asthe eluent. There was obtained 0.082 g (30%) of4-amino-N-(6-methylamino-2-pyrrolidin-1-yl-pyrimidin-4-yl)-benzenesulfonamideas beige crystals; m.p. 299-301° C.

EXAMPLE 24

4-Amino-N-(6-amino-2-mercapto-pyrimidin-4-yl)-benzenesulfonamide

1 g (0.0043 mol) of 4-acetamino-benzenesulfochloride was dissolved in 20ml of pyridine and treated with 0.64 g (0.0045 mol) of4,6-diamino-pyrimidine-2-thiol. The mixture was stirred at roomtemperature for 2 hours., poured into 30 ml of water, the precipitatewas filtered off under suction and dissolved in 40 ml of 1N NaOH. Thereaction mixture was boiled at reflux for 2 hours., filtered, thefiltrate was treated with 1N HCl to pH 6 and the precipitate whichseparated was filtered off. This was washed well with water and dried.There was obtained 0.96 g (75%) of4-amino-N-(6-amino-2-mercapto-pyrimidin-4-yl)-benzenesulfonamide asyellowish crystals; m.p.: 232-234° C.

EXAMPLE 25

4-Amino-N-(2-amino-6-methoxy-pyrimidin-4-yl)-benzenesulfonamide

0.27 g (0.0009 mol) of4-amino-N-(2-amino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide wasdissolved in a solution of 0.23 g of sodium in 20 ml of methanol andstirred in an autoclave at 150° C. for 9 hours. The solvent wasdistilled off, the residue was added to water and the pH value wasadjusted to 4-5 with 1N HCl. The precipitate which thereby separated wasfiltered off under suction, washed with water and dried. The crystalsobtained were triturated in 20 ml of methanol, again filtered off anddried in a high vacuum. There was obtained 0.25 g (94%) of4-amino-N-(2-amino-6-methoxy-pyrimidin-4-yl)-benzenesulfonamide as beigecrystals; m.p.: >250° C. (dec.).

EXAMPLE 26

4-Amino-N-(4,6-bis-methylamino-pyrimidin-2-yl)-benzenesulfonamide

0.25 g (0.0008 mol) of4-amino-N-(4,6-dimethoxy-pyrimidin-2-yl)-benzenesulfonamide wasdissolved in 20 ml of 8M methylamine in ethanol and stirred in anautoclave at 130° C. for 21 hours. Thereafter, the reaction mixture wasconcentrated, the residue was suspended in 5 ml of ethanol, treated inan ultrasound bath and the precipitate was filtered off. This wasdissolved in 5 ml of 1N NaOH, the solution was filtered and the pH valuewas adjusted to 5 with 1N HCl. The precipitate which thereby separatedwas filtered off and dried. There was obtained 0.1 g (42%) of4-amino-N-(4,6-bis-methylamino-pyrimidin-2-yl)-benzenesulfonamide asyellow crystals; m.p.: 262-263° C.

EXAMPLE 27

N-(2,6-Bis-methylamino-pyrimidin-4-yl)-4-chloro-benzenesulfonamide

0.39 g (0.0022 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 1.0g (0.0044 mol) of 4-chloro-benzene-sulfonamide potassium salt werestirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8 hours. Then,the solvent was distilled off in a high vacuum, the residue waspartitioned in ethyl acetate/water and extracted. The aqueous phase wassaturated with sodium chloride, evaporated briefly in a vacuum, madeacid with 4N HCl and extracted with dichloromethane. The two extractswere combined and chromatographed over silica gel with cyclohexane/ethylacetate 1:1 as the eluent. There was obtained 0.62 g (85%) of4-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide aswhite crystals. m.p. 196-198° C.

0.62 g (0.0019 mol) of4-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamidewas dissolved in 10 ml of ethanol, treated with 1.67 g (0.025 mol) ofmethylamine hydrochloride and 6.2 ml (0.044 mol) of triethylamine andstirred in an autoclave at 140° C. for 18 hours. The mixture was freedcompletely from solvent, the residue was partitioned in ethylacetate/water and the insoluble constituents were filtered off undersuction. The filter cake was recrystallized in methanol/diethyl ether.There was obtained 0.28 g (45%) ofN-(2,6-bis-methylamino-pyrimidin-4-yl)-4-chloro-benzenesulfonamide aswhite crystals; m.p. 272-273° C.

EXAMPLE 28

N-(2,6-Bis-methylamino-pyrimidin-4-yl)-4-tert-butyl-benzenesulfonamide

0.39 g (0.0022 mol) of (4,6-dichloro-pyrimidin-2-yl)methylamine and 1.1g (0.0044 mol) of 4-tert-butyl-benzenesulfonamide potassium salt werestirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8 hours. Then,the solvent was distilled off in a high vacuum, the residue waspartitioned in ethyl acetate/water and extracted. The aqueous phase wassaturated with sodium chloride, de-gassed in a vacuum and made acid with4N HCl, with a precipitate separating. The mixture was suction filtered,the extract and the solid were combined and chromatographed over silicagel with cyclohexane/ethyl acetate 2:1 as the eluent. The product wasrecrystallized from ethyl acetate/n-hexane. There was obtained 0.57 g(73%) of4-tert-butyl-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamideas white crystals; m.p.: 118-137° C. (dec.).

0.47 g (0.0013 mol) of4-tert-butyl-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamidewas dissolved in 10 ml of ethanol, treated with 1.3 g (0.019 mol) ofmethylamine hydrochloride and 4.7 ml (0.034 mol) of triethylamine andstirred in an autoclave at 140° C. for 18 hours. The mixture was freedcompletely from solvent, the residue was partitioned in ethylacetate/water and the insoluble constituents were filtered off undersuction. The filtered cake was recrystallized in methanol/diethyl ether.There was obtained 0.15 g (33%) ofN-(2,6-bis-ethylamino-pyrimidin-4-yl)-4-tert-butyl-benzenesulfonamide aswhite crystals; m.p. 316-318° C.

EXAMPLE 29

N-(2,6-Bis-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamide

0.46 g (0.0026 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 1.1g (0.0051 mol) of 4-fluoro-benzenesulfonamide potassium salt werestirred in 10 ml of 1-methyl-2-pyrrolidone in 150° C. for 8 hours. Then,the solvent was distilled off in a high vacuum, the residue waspartitioned in ethyl acetate/water and extracted. The aqueous phase wassaturated with sodium chloride, evaporated briefly in a vacuum and madeacid with 4N HCl, with a precipitate separating. The mixture wassuctioned filtered, the extract and the solid were combined andchromatographed over silica gel with cyclohexane/ethyl acetate 2:1 asthe eluent. The product was recrystallized from ethyl acetate/n-hexane.There was obtained 0.46 g (56%) ofN-(6-chloro-2-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamide aswhite crystals; m.p. 121-123C.

0.36 g (0.0011 mol) ofN-(6-chloro-2-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamidewas dissolved in 10 ml of ethanol, treated with 1.2 g (0.018 mol) ofmethylamine hydrochloride and 4.0 ml (0.029 mol) of triethylamine andstirred in an autoclave at 140° C. for 17 hours. The mixture was freedcompletely from solvent, the residue was partitioned in ethylacetate/water, the insoluble constituents were filtered off undersuction and extracted. The extract and the solid were combined andrecrystallized from methanol/diethyl ether. There was obtained 0.15 g(43%) ofN-(2,6-bis-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamide aswhite crystals; m.p. 261-263° C.

EXAMPLE 30

N-(2,6-Bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide

5.38 g (0.0275 mol) of benzenesulfonamide potassium salt and 2.45 g(0.0138 mol) of 2-methylamino-4,6-dichloro-pyrimidine were suspended in22 ml of 1-methyl-2-pyrrolidone and stirred at 150° C. for 24 hours. Thesolvent was removed in a high vacuum and the residue was suspended in250 ml of water. The mixture was extracted three times with 100 ml ofethyl acetate each time and the combined organic phases were washed with200 ml of saturated NaHCO₃. The combined aqueous phases were made acidwith 3N HCl and the precipitate which thereby separated was filtered offunder suction. It was chromatographed on silica gel withdichloromethane/methanol 99:1→98:2. The yellowish crystals obtainedafter the chromatography were suspended in 70 ml of 1N NaOH, thesuspension was filtered and the clear filtrate was adjusted to pH 3.5with 1N HCl. The precipitate which thereby separated was isolated anddried. There were obtained 1.9 g (46%) ofN-(2-methylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide ascolorless crystals; m.p.: 186-187° C.

0.25 g (0.00084 mol) ofN-(2-methylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide wasdissolved in 20 ml of 2M methylamine in THF and stirred in an autoclaveat 130° C. for 3 hours. The mixture was freed from solvent, the residuewas dissolved in 25 ml of 2N NaOH, filtered and the pH value of thefiltrate was adjusted to 6 with 1N HCl. The precipitate was filtered offunder suction, dried and chromatographed on silica gel withdichloromethane/methanol 95:5. There was obtained 0.09 g (36%) ofN-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide as yellowishcrystals; m.p.: >260° C. (dec).

EXAMPLE 31

N-(2,6-Bis-methylamino-pyrimidin-4-yl)-4-methyl-benzenesulfonamide

0.30 g (0.00097 mol) ofN-(2,6-dimethoxy-pyrimidin-4-yl)-4-methyl-benzenesulfonamide wasdissolved in 30 ml of 33 per cent ethanolic methylamine and stirred inan autoclave at 140° C. for 24 hours. The mixture was cooled and suctionfiltered. There was obtained 0.125 g (42%) ofN-(2,6-bis-methylamino-pyrimidin-4-yl)-4-methyl-benzenesulfonamide asgrey crystals; m.p. 270-272° C.

EXAMPLE 32

N-(2,6-Bis-methylamino-pyrimidin-4-yl)-3-chloro-benzenesulfonamide

0.24 g (0.00135 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and0.62 g (0.0027 mol) of 3-chloro-benzene-sulfonamide potassium salt werestirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8 hours. Then,the solvent was distilled off in a high vacuum, the residue waspartitioned in ethyl acetate/water and extracted. The aqueous phase wasmade acid with 4N HCl and extracted with dichloromethane. The residuewas chromatographed over silica gel with cyclohexane/ethyl acetate 2:1as the eluent. There was obtained 0.24 g (53%) of3-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide asyellow crystals; m.p. 120-130° C. (dec.).

0.10 g (0.00030 mol) of3-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamidewas dissolved in 5 ml of EtOH, treated with 0.27 g (0.004 mol) ofmethylamine hydrochloride and 1 ml (0.007 mol) of triethylamine andstirred in an autoclave at 145° C. for 17 hours. The entire reactionmixture was partitioned in ethyl acetate/water and extracted. Theresidue was recrystallized from MeOH. There was obtained 0.04 g (41%) ofN-(2,6-bis-methylamino-pyrimidin-4-yl)-3-chloro-benzenesulfonamide aswhite crystals; m.p. 167-168° C.

EXAMPLE 33

N-(2,6-Bis-methylamino-pyrimidin-4-yl)-3-trifluoromethyl-benzenesulfonamide

0.27 g (0.00155 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and0.82 g (0.0031 mol) of 3-trifluoromethyl-benzenesulfonamide potassiumsalt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8hours. Then, the solvent was distilled off in a high vacuum, the residuewas partitioned in ethyl acetate/water and extracted. The aqueous phasewas made acid with 4N HCl and extracted with dichloromethane. Theresidue was chromatographed over silica gel with cyclohexane/ethylacetate 2:1 as the eluent. There was obtained 0.26 g (69%) ofN-(6-chloro-2-methylamino-pyrimidin-4-yl)-3-trifluoromethyl-benzenesulfonamideas white/beige crystals; m.p.: 190-193° C.

0.10 g (0.00027 mol) ofN-(6-chloro-2-methylamino-pyrimidin-4-yl)-3-trifluoromethyl-benzenesulfonamidewas dissolved in 5 ml of EtOH, treated with 0.27 g (0.004 mol) ofmethylamine hydrochloride and 1 ml (0.007 mol) of triethylamine andstirred in an autoclave at 145° C. for 17 hours. The entire reactionmixture was partitioned in ethyl acetate/water and extracted. Theresidue was recrystallized in MeOH. There was obtained 0.055 g (56%) ofN-(2,6-bis-methylamino-pyrimidin-4-yl)-3-trifluoromethyl-benzenesulfonamideas white crystals; m.p. 234-235° C.

EXAMPLE 34

4-Amino-N-(3.5-diamino-phenyl)-benzenesulfonamide

0.105 g (0.00033 mol) ofN-[4-(3,5-diamino-phenylsulfamoyl)-phenyl]-acetamide was dissolved in6.5 ml of 1N NaOH and boiled at reflux for 15 hours. The reactionmixture was treated with 50 ml of saturated ammonium chloride solutionand extracted twice with 100 ml of ethyl acetate each time. The combinedorganic phases were washed with saturated sodium chloride solution anddried over MgSO₄. After removal of the solvent the residue waschromatographed on aluminium oxide (neutral, activity 1), firstly with5% and then 10% methanol in dichloromethane. There was obtained 0.05 g(55%) of 4-amino-N-(3,5-diamino-phenyl)benzenesulfonamide as a beigesolid; m.p.: 188-190° C.

EXAMPLE 35

4-Amino-N-(3,5-bis-methylamino-phenyl)-benzenesulfonamide hydrochloride

0.24 g (0.001 mol) of N-(3-acetylamino-5-nitro-phenyl)-acetamide wassuspended in 20 ml of THF, treated with 0.092 g (0.0023 mol) of NaH and10 ml of DMF and stirred at room temperature for 15 hours. Then, 0.29 ml(0.0046 mol) of methyl iodide was added thereto and the mixture wasstirred for a further 48 hours. Subsequently, the solvent was distilledoff, the residue was taken up in 100 ml of water, extracted four timeswith 80 ml of ethyl acetate each time, the combined organic phases werewashed with saturated sodium chloride solution and dried over sodiumsulfate. After removal of the solvent the residue was chromatographed onsilica gel with 3% methanol in dichloromethane. There was obtained 0.2 g(75%) of N-[3-(acetyl-methyl-amino)-5-nitro-phenyl]-N-methyl-acetamideas a brown oil. MS (EI): me/e=265 (C₁₂ H₁₅ N₃ O₄ ⁺).

0.19 g (0.00072 mol) ofN-[3-(acetyl-methyl-amino)-5-nitro-phenyl]-N-methyl-acetamide wasdissolved in 15 ml of ethanol, treated with 0.019 g of Pd/C (10%) andhydrogenated with hydrogen gas at room temperature for 2 hours. Thecatalyst was filtered off, the solvent was distilled off and the residuewas chromatographed on silica gel with ethyl acetate. There was obtained0.16 g (94%) ofN-[3-(acetyl-methyl-amino)-5-amino-phenyl]-N-methyl-acetamide as whitecrystals; m.p.: 179-181° C.

0.15 g (0.00063 mol) ofN-[3-(acetyl-methyl-amino)-5-amino-phenyl]N-methyl-acetamide wasdissolved in 3 ml of pyridine, treated with 0.154 g (0.00064 mol) of4-acetamino-benzenesulfochloride and stirred at room temperature for 16hours. Subsequently, the mixture was freed from solvent, the residue wastaken up in 25 ml of water, extracted four times with 200 ml of ethylacetate each time and the combined organic phases were washed withsaturated sodium chloride solution and dried over sodium sulfate. Afterremoval of the solvent the residue was chromatographed on silica gel,firstly with 2% and then 5% methanol in dichloromethane. There wasobtained 0.15 g (55%) ofN-[3-(4-acetylamino-phenylsulfonylamino)-5-(acetyl-methyl-amino)-phenyl]-N-methyl-acetamideas an orange colored, amorphous solid. MS (ISN): me/e=431 (C₂₀ H₂₃ N₄ O₅S⁻).

0.113 g (0.00026 mol) ofN-[3-(4-acetylamino-phenylsulfonylamino)-5-(acetyl-methyl-amino)-phenyl]-N-methyl-acetamidewas dissolved in 10 ml of 1N NaOH and boiled at reflux for 2 hours. Themixture was neutralized with 1N HCl, extracted with ethyl acetate andthe organic phase was dried over sodium sulfate. After removal of thesolvent the residue was dissolved in 4 ml of methanol and treated with 3ml of 2M HCl. After the addition of 7-8 ml of ethyl acetate the productseparated out slowly. It was filtered off and dried in a vacuum. Therewas obtained 0.085 g (74%) of4-amino-N-(3,5-bis-methylamino-phenyl)-benzenesulfonamide hydrochloride(1:2.6) as a pink coloured amorphous solid. MS (ISN): me/e=305 (C₁₄ H₁₇N₄ O₂ S⁻).

EXAMPLE 36

4-Amino-N-(3-methylamino-phenyl)-benzenesulfonamide

1.3 g (0.0079 mol) of N-(3-amino-phenyl)-benzenesulfonamide weredissolved in 50 ml of pyridine, treated with 1.94 g (0.0083 mol) of4-acetamino-benzenesulfochloride and stirred at room temperature for 18hours. The pyridine was distilled off, the residue was suspended inwater and filtered under suction. The material on the suction filter waswashed well with water and dried in a high vacuum. There were obtained2.7 g (94%) ofN-[4-[3-(acetyl-methyl-amino)-phenylsulfamoyl]-phenyl]-acetamide as alight yellow colored solid; m.p.: 258-260° C.

2.5 g (0.0069 mol) ofN-[4-[3-(acetyl-methyl-amino)-phenylsulfamoyl]-phenyl]-acetamide weredissolved in 150 ml of 1N NaOH and boiled in reflux for 4 hours.Subsequently, the pH value was adjusted to 4 with 1N HCl and theprecipitate which separated was filtered off. After drying the materialon the suction filter was chromatographed on silica gel with 3% methanolwith dichloromethane. There were obtained 1.64 g (85%) of4-amino-N-(3-methylamino-phenyl)-benzenesulfonamide as a yellowishsolid; m.p.: 134-135° C.

EXAMPLE 37

N-(3,5-Dimethoxy-phenyl)-3-trifluoromethyl-benzenesulfonamide

0.31 g (0.002 mol) of 3,5-dimethoxyaniline was dissolved in 10 ml ofpyridine, treated with 0.54 g (0.0022 mol) of3-trifluoromethyl-benzenesulfochloride and stirred for 2 hours. at roomtemperature. After removal of the solvent the residue was taken up inwater, extracted with ethyl acetate, the organic phase was washed withsaturated sodium chloride solution and dried over sodium sulfate. Thesolvent was evaporated and the residue was chromatographed on silica gelwith hexane/ethyl acetate 2:1. There was obtained 0.68 g (94%) ofN-(3,5-dimethoxy-phenyl)-3-trifluoromethyl-benzenesulfonamide as whitecrystals; m.p.: 78-81° C.

EXAMPLE 38

4-Amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide

5.1 g (0.02 mol) of 4-amino-2,6-dibromo-pyridine were dissolved in 100ml of pyridine, treated with 7.1 g (0.03 mol) of4-acetamino-benzenesulfochloride and stirred at 60° C. for 16 hours.After removal of the solvent the residue was taken up in 100 ml of 1NHCl, extracted twice with 100 ml of ethyl acetate each time, thecombined organic phases were washed with saturated sodium chloridesolution and dried over sodium sulfate. Then, the mixture was freed fromsolvent and the residue was dried in a high vacuum. There were obtained7.2 g (79%) ofN-[4-(2,6-dibromo-pyridin-4-ylsulfamoyl)-phenyl]-acetamide as yellowcrystals; m.p.: >260° C. (dec.).

6.2 g (0.0138 mol) ofN-[4-(2,6-dibromo-pyridin-4-ylsulfamoyl)-phenyl]-acetamide weredissolved in 138 ml of 1N NaOH and boiled at reflux for 2 hours. Aftercooling the mixture was adjusted to pH 6 with 2N HCl and the precipitatewhich separated was filtered off. The material on the suction filter waswashed well with water and dried. It was subsequently chromatographed on:silica gel with ethyl acetate/hexane 1:2→1:1. There were obtained 4.86g (86%) of 4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide asbeige crystals; m.p.: 220-222° C.

EXAMPLE 39

4-Amino-N-(2-chloro-6-methylamino-pyridin-4-yl)-benzenesulfonamidedihydrochloride

0.82 g (0.005 mol) of 4-amino-2,6-dichloro-pyridine was dissolved in 25ml of pyridine, treated with 1.3 g (0.0055 mol) of4-acetamino-benzenesulfochloride and stirred at 60° C. for 16 hours.After removal of the solvent the residue was taken up in 50 ml of 1NHCl, extracted twice with 50 ml of ethyl acetate each time, the combinedorganic phases were washed with saturated sodium chloride solution anddried over sodium sulfate. Then, the mixture was freed from solvent andthe residue was chromatographed on silica gel with ethyl acetate/hexane4:1. There were obtained 1.45 g (80%) ofN-[4-(2,6-dichloro-pyridin-4-ylsulfamoyl)-phenyl]-acetamide as yellowcrystals; m.p.: >246° C. (dec.).

1.25 g (0.0035 mol) ofN-[4-(2,6-dichloro-pyridin-4-ylsulfamoyl)-phenyl]-acetamide weredissolved in 35 ml of 1N NaOH and boiled at reflux for 2 hours. Aftercooling the mixture was adjusted to pH 6 with 2N HCl and the precipitatewhich separated was filtered off. The material on the suction filter waswashed well with water and dried. It was subsequently chromatographed onsilica gel with ethyl acetate/hexane 1:2→1:1. There were obtained 1.04 g(93%) of 4-amino-N-(2,6-dichloro-pyridin-4-yl)-benzenesulfonamide aswhite crystals; m.p.: 209-211° C. (dec.).

0.11 g (0.00035 mol) of4-amino-N-(2,6-dichloro-pyridin-4-yl)-benzenesulfonamide was stirred in25 ml of liquid methylamine in an autoclave at 130° C. for 72 hours.After removal of the methylamine the residue was taken up in 5 ml ofdichloromethane/methanol 1:1, filtered and, after removal of thesolvent, chromatographed on silica gel with hexane/ethyl acetate 3:1,2:1 and finally 1:1. The product, obtained as a white, amorphous solidsubstance, was dissolved in 2 ml of methanol, treated with 2 ml of 2NHCl/methanol, diluted with 20 ml of diethyl ether and filtered off undersuction. The material on the suction filter was washed well with diethylether and dried in a high vacuum. There was obtained 0.055 g (41%) of4-amino-N-(2-chloro-6-methylamino-pyridin-4-yl)-benzenesulfonamidedihydrochloride (1:2) as white crystals; m.p.: >215° C. (dec.).

EXAMPLE 40

4-Amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamidehydrochloride

0.81 g (0.002 mol) of4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide was stirred in35 ml of liquid methylamine in an autoclave at 130° C. for 44 hours. Themethylamine was left to evaporate, the residue was dissolved in ethanol,treated with 2 g of silica gel, concentrated and the residue waschromatographed on silica gel, firstly with ethyl acetate/hexane 1:2,then with pure ethyl acetate. There was obtained 0.63 g (88%) of4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide as abeige foam. 0.33 g (0.00092 mol) of this was dissolved in 10 ml ofmethanol, treated with 5 ml of 2M HCl in methanol, concentrated andagain treated with 4 ml of methanol. The precipitate obtained wasfiltered off under suction, rinsed with a small amount of methanol anddried in a high vacuum. There was obtained 0.27 g (69%) of4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamidehydrochloride as white crystals; m.p.: 226-228° C. (dec.).

EXAMPLE 41

4-Amino-N-(2-bromo-6-ethylamino-pyridin-4-yl)-benzenesulfonamide

5.1 g (0.0125 mol) of4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide were stirred in100 ml of liquid ethylamine in an autoclave at 150° C. for 24 hours. Theethylamine was left to evaporate, the residue was dissolved in ethanol,treated with 5 g of silica gel, concentrated and the residue waschromatographed on silica gel, firstly with ethyl acetate/hexane 1:2 andthen 1:1. There were obtained 2.15 g of a brown oil which was suspendedin 200 ml of 25% HCl. The mixture was suction filtered, the filtrate wasadjusted to pH 8 with ZN NaOH and the precipitate which separated wasisolated. After drying in a high vacuum there was obtained 0.96 g (21%)of 4-amino-N-(2-bromo-6-ethylamino-pyridin-4-yl)-benzenesulfonamide asbeige crystals; m.p.: >85° C. (dec.).

EXAMPLE 42

4-Amino-N-(2,6-bis-methylamino-pyridin-4-yl)-benzenesulfonamidehydrochloride

0.90 g (0.002 mol) of4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide was stirred in35 ml of liquid methylamine in an autoclave at 160° C. for 16 hours. Themethylamine was left to evaporate, the residue was dissolved in ethanol,treated with 1 g of silica gel, concentrated and the residue waschromatographed on silica gel, firstly with ethyl acetate/hexane 1:1 andthen with pure ethyl acetate. There was obtained 0.34 g of a brown oilwhich was suspended in 100 ml of 1N NaOH. The mixture was suctionfiltered, the filtrate was adjusted to pH 8 with 1N HCl and theprecipitate which separated was isolated. After drying with a highvacuum there was obtained 0.22 g (35%) of4-amino-N-(2,6-bis-methylamino-pyridin-4-yl)-benzenesulfonamidehydrochloride (1:3) as beige crystals; m.p.: >280° C. (dec.). These weredissolved in 5 ml of methanol and treated with 3 ml of 2N methanolicHCl. The precipitate which separated was filtered off and dried. Therewas obtained 0.13 g of4-amino-N-(2,6-bis-methylamino-pyridin-4-yl)-benzenesulfonamidehydrochloride (1:3) as light beige crystals; m.p.: 197° C. (dec.).

EXAMPLE 43

4-Amino-N-(2-ethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamide

2.5 g (0.007 mol) of4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide werestirred with 80 ml of ethylamine in an autoclave at 160° C. for 40hours. The residual ethylamine was left to evaporate and the residue waschromatographed on silica gel with ethyl acetate/hexane 1:2, then 2:3and finally 1:1. The thus-obtained 0.67 g of brown oil was suspended in200 ml of 1N NaOH, suction filtered and the filtrate was neutralizedwith 1N HCl. It was again suction filtered, the filtrate was saturatedwith NaCl and extracted with ethyl acetate. The organic phase was dried.There was obtained 0.055 g (2.5%) of4-amino-N-(2-ethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamideas pale brown crystals; MS (ISN): me/e=320 (C₁₄ H₁₈ N₅ O₂ S⁻).

EXAMPLE 44

4-Amino-N-(2-dimethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamide

2.5 g (0.007 mol) of4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide werestirred with 80 ml of dimethylamine in an autoclave at 160° C. for 7hours. The residual dimethylamine was left to evaporate and the residuewas chromatographed on silica gel with ethyl acetate/hexane 1:1, then2:1 and finally 3:1. The polar fractions were chromatographed twice onsilica gel with ethyl acetate/hexane 2:3 and 1:1 as the eluent. Therewas obtained 0.175 g (8%) of4-amino-N-(2-dimethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamideas beige crystals: MS (ISP): me/e=322 (C₁₄ H₂₀ N₅ O₂ S⁺).

EXAMPLE 45

4-Amino-N-(2.6-bis-ethylamino-pyridin-4-yl)-benzenesulfonamide

5.1 g (0.0125 mol) of4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide were stirred in100 ml of liquid ethylamine in an autoclave at 150° C. for 24 hours. Theethylamine was left to evaporate, the residue was dissolved in ethanol,treated with 5 g of silica gel, concentrated and the residue waschromatographed on silica gel, firstly with ethyl acetate/hexane 1:2,then 1:1 and finally 2:1. There were obtained 1:16 g of a brown solidwhich was suspended in 500 ml of 1N NaOH. The mixture was filtered, thefiltrate was adjusted to pH 8, again filtered and the filtrate wasextracted with ethyl acetate. The filter material of the last filtrationwas combined with the ethyl acetate phase, concentrated and the residuewas chromatographed on silica gel with ethyl acetate/hexane 2:1. Therewas obtained 0.22 g of a brown coloured solid which was suspended in 20ml of 1N NaOH. The mixture was again filtered, the filtrate was adjustedto pH 8 with 1N HCl and the product which separated was filtered offunder suction. There was obtained 0.14 g (3%) of4-amino-N-(2,6-bis-ethylamino-pyridin-4-yl)-benzenesulfonamide as beigecrystals; m.p.: 212-215° C. (dec.).

EXAMPLE 46

4-Amino-N-(2-methylamino-pyridin-4-yl)-benzenesulfonamide

0.5 g (0.0014 mol) of4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide wasdissolved in 25 ml of ethanol, treated with 0.05 g of Pd/C andhydrogenated with hydrogen gas under normal pressure for 1 hour. Thecatalyst was filtered off, the filtrate was concentrated and the residuewas dissolved in 10 ml of 1N NaOH, filtered and the filtrate was thenadjusted pH 8 by means of 1N HCl. The precipitate which separated slowlywas filtered off under suction, rinsed and dried in a high vacuum. Therewas obtained 0.22 g (57%) of4-amino-N-(2-methylamino-pyridin-4-yl)-benzenesulfonamide as whitecrystals; m.p.: >261° C. (dec).

EXAMPLE 47

4-Amino-N-(2,6-bis-dimethylamino-pyridin-4-yl)-benzenesulfonamide

0.81 g (0.002 mol) of4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide was stirred in30 ml of dimethylamine in an autoclave in 160° C. for 45 hours. Theexcess dimethylamine was left to evaporate, the residue was dissolved ina mixture of methanol and ethyl acetate, treated with 1 g of silica gel,concentrated and the residue was chromatographed on silica gel, firstlywith ethyl acetate/hexane 1:3 and then 1:2. After drying in a highvacuum there was obtained 0.67 g (100%) of4-amino-N-(2,6-bis-dimethylamino-pyridin-4-yl)-benzenesulfonamide asbeige crystals; m.p.: 157-160° C. (dec.).

EXAMPLE 48

N-(2,6-Bis-methylamino-pyridin-4-yl)-4-chloro-benzenesulfonamidedihydrochloride

3.0 g (0.012 mol) of 4-amino-2,6-dibromo-pyridine were dissolved in 60ml of pyridine, treated with 2.76 g (0.013 mol) of4-chloro-benzenesulfochloride and stirred at 60° C. for 5 hours. Afterremoval of the solvent the residue was taken up in 100 ml of 1N HCl,extracted twice with 100 ml of ethyl acetate each time, the combinedorganic phases were washed with saturated sodium chloride solution anddried over sodium sulfate. The mixture was freed from solvent and theresidue was chromatographed on silica gel with ethyl acetate/hexane 1:4and then 1:1. There were obtained 4.4 g (87%) of4-chloro-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide as yellowcrystals. For analytical purposes, 0.2 g (0.0005 mol) was recrystallizedfrom tert-butyl methyl ether; m.p.: 203-205° C. (dec.).

0.50 g (0.0017 mol) of4-chloro-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide was stirred in35 ml of liquid methylamine with 0.025 g of Cu powder in an autoclave at80° C. for 18 hours. The methylamine was left to evaporate, the residuewas dissolved in 50 ml of water, the pH value was adjusted to 8 and themixture was extracted three times with 100 ml of ethyl acetate eachtime. The combined organic phases were washed with saturated sodiumchloride solution and dried over sodium sulfate. They were concentratedand the residue was suspended in 1N NaOH. After filtration the clearfiltrate was saturated with NaCl and acidified to pH 1 with 1N HCl. Abeige precipitate thereby separated and was isolated. There was obtained0.24 g (50%) ofN-(2,6-bis-methylamino-pyridin-4-yl)-4-chloro-benzenesulfonamidedihydrochloride as beige crystals; m.p.: >170° C. (dec).

EXAMPLE 49

3-Chloro-N-(2,6-bis-methylamino-pyridin-4-yl)-benzenesulfonamide

2.0 g (0.0079 mol) of 4-amino-2,6-dibromo-pyridine were dissolved in 24ml of pyridine, treated with 2.5 g (0.012 mol) of3-chloro-benzenesulfochloride and stirred at 60° C. for 5 hours. Afterremoval of the solvent the residue was taken up in 100 ml of 1N HCl,extracted twice with 100 ml of ethyl acetate each time, the combinedorganic phases were washed with saturated sodium chloride solution anddried over sodium sulfate. The mixture was freed from solvent and theresidue was chromatographed on silica gel with ethyl acetate/hexane 1:2,then 1:1 and finally 2:1. There were obtained 2.12 g (63%) of3-chloro-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide as yellowcrystals; m.p.: 187-189° C.

1.0 g (0.0023 mol) of3-chloro-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide was stirred in35 ml of liquid methylamine in an autoclave at 160° C. for 18 hours. Themethylamine was left to evaporate, the residue was dissolved in water,the pH value was adjusted to 8 and the mixture was extracted three timeswith 100 ml of ethyl acetate each time. The combined organic phases werewashed with saturated sodium chloride solution and dried over sodiumsulfate. The solvent was evaporated and the residue was chromatographedon silica gel, firstly with ethyl acetate/hexane 2:1, then with pureethyl acetate and finally with ethyl acetate/methanol 1:1. Subsequently,the product fraction was again chromatographed on silica gel withhexane/ethyl acetate 1:1. There was obtained 0.165 g (22%) of3-chloro-N-(2,6-bis-methylamino-pyridin-4-yl)-benzenesulfonamide aslight reddish coloured crystals. 0.13 g (0.0004 mol) of these weresuspended in 20 ml of 1N NaOH, filtered and the clear filtrate wasadjusted to pH 8 with 1N HCl. The precipitate which thereby separatedwas filtered off under suction and dried in a high vacuum. There wasobtained 0.11 g (15%) of3-chloro-N-(2,6-bis-methylamino-pyridin-4-yl)-benzenesulfonamide; m.p.:133° C. (dec.).

EXAMPLE 50

N-(2,6-Bis-methylamino-pyridin-4-yl)-3-trifluoromethyl-benzenesulfonamidedihydrochloride

3.0 g (0.0012 mol) of 4-amino-2,6-dibromo-pyridine were dissolved in 60ml of pyridine, treated with 2.1 ml (0.013 mol) of3-trifluoromethyl-benzenesulfochloride and stirred at 60° C. for 5hours. After removal of the solvent the residue was taken up in 100 mlof water, extracted twice with 100 ml of diethyl ether each time, thecombined organic phases were washed with saturated sodium chloridesolution and dried over sodium sulfate. The mixture was freed fromsolvent and the residue was chromatographed on silica gel with ethylacetate/hexane 1:2 and then 1:1. There were obtained 4.77 g (87%) ofN-(2,6-dibromo-pyridin-4-yl)-3-trifluoromethyl-benzenesulfonamide aspale yellow crystals. By crystallization in tert-butyl methyl etherthere was obtained an analytically pure sample; m.p. 149-151° C.

0.50 g (0.0011 mol) ofN-(2,6-dibromo-pyridin-4-yl)-3-trifluoromethyl-benzenesulfonamide wasstirred in 35 ml of liquid methylamine with 0.022 g of Cu powder in anautoclave at 80° C. for 18 hours. The methylamine was left to evaporate,the residue was dissolved in 50 ml of water, the pH value was adjusted 8with 1N HCl and the mixture was extracted three times with 100 ml ofethyl acetate each time. The combined organic phases were washed withsaturated sodium chloride solution and dried over sodium sulfate. Themixture was concentrated and the residue was chromatographed on silicagel with ethyl acetate/hexane 1:9, 1:4, 1:1 and 1:0. The fractionobtained with pure ethyl acetate was suspended in 1N NaOH. Afterfiltration the clear filtrate was saturated with NaCl and acidified topH 1 with 1N HCl. A beige precipitate thereby separated and wasisolated. There was obtained 0.094 g (15%) ofN-(2,6-bis-methylamino-pyridin-4-yl)-3-trifluoromethyl-benzenesulfonamidedihydrochloride as beige crystals; m.p.: >227° C. (dec.).

EXAMPLE 51

4-Amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide

1.54 g (0.0082 mol) of 4-amino-2-bromo-6-methyl-pyridine were dissolvedin 25 ml of pyridine, treated with 2.9 g (0.0124 mol) of4-acetamino-benzenesulfochloride and stirred at 60° C. for 16 hours.After removal of the solvent the residue was chromatographed on silicagel with ethyl acetate as the eluent. The product-containing fractionswere freed from solvent and dried in a high vacuum. There were obtained2.17 g (69%) ofN-[4-(2-bromo-6-methyl-pyridin-4-ylsulfamoyl)-phenyl]-acetamide ascolourless crystals; m.p.: 262-264° C. (dec.).

1.15 g (0.003 mol) ofN-[4-(2-bromo-6-methyl-pyridin-4-ylsulfamoyl)-phenyl]-acetamide weredissolved in 15 ml of 2N NaOH and boiled at reflux for 1 hour. Aftercooling the mixture was acidified to pH 5 with 2N HCl and the colourlessprecipitate which separated was filtered off. The material on thesuction filter was washed with copious water and dried. There wasobtained 0.95 g (93%) of4-amino-N-(2-bromo-6-methyl-pyridin-4-yl)-benzenesulfonamide ascolorless crystals; m.p.: >110° C. (dec.).

0.94 g (0.00275 mol) of4-amino-N-(2-bromo-6-methyl-pyridin-4-yl)-benzenesulfonamide was stirredin 50 ml of 8M methylamine in ethanol in an autoclave at 135° C. for 40hours. The methylamine was allowed to evaporate, the residue wasdissolved in ethanol, treated with 2 g of silica gel, concentrated andthe residue was chromatographed on silica gel, firstly with ethylacetate/hexane 1:1, then 9:1. There was obtained 0.39 g (48%) of4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide ascolourless crystals; m.p.: 173-175° C. 0.081 g (0.00028 mol) thereof wasrecrystallized from methanol, diethyl ether and hexane, dried in a highvacuum, dissolved in 3 ml of methanol and treated with 2.8 ml of 0.1NNaOH. The methanol was distilled off and the residue was freeze-driedtwice. There was obtained 0.084 g (97%) of4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamidesodium salt (1:1) as white crystals; MS (ISP): me/e=293 (C₁₃ H₁₇ N₄ O₂S⁺). 0.31 g (0.0011 mol) of4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide wasdissolved in 2 ml of methanol, treated with 1 ml of 2.4N HCl in diethylether and freed from solvent. The residue was dissolved in 1 ml ofmethanol and slowly added dropwise to diethyl ether while stirringvigorously. A colourless precipitate thereby separated and this wasisolated and dried in a high vacuum. There was obtained 0.33 g (87%) of4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamidehydrochloride (1:1.86) as white crystals; m.p.: >170° C. (dec.).

EXAMPLE 52

4-Amino-N-(1H-indol-4-yl)-benzenesulfonamide

0.095 g (0.00072 mol) of 4-amino-1H-indole was dissolved in 3 ml ofpyridine, treated with 0.20 g (0.00086 mol) of4-acetamino-benzenesulfochloride and stirred at 60° C. for 16 hours.After removal of the solvent the residue was taken up in 10 ml of 1NHCl, extracted twice with 20 ml of ethyl acetate each time, the combinedorganic phases were washed with saturated sodium chloride solution anddried over sodium sulfate. Then, the mixture was freed from solvent andthe residue was dried in a high vacuum. There was obtained 0.155 g (65%)of N-[4-(1H-indol-4-yisulfamoyl)-phenyl]-acetamide as pale greycrystals; m.p.: >260° C.

0.15 g (0.00045 mol) of N-[4-(1H-indol-4-ylsulpjamoyl)-phenyl]-acetamidewas dissolved in 4 ml of 1N NaOH and boiled at reflux for 1 hour. Aftercooling the mixture was adjusted to pH 6 with 0.1N HCl and theprecipitate which separated was filtered off. The material on thesuction filter was washed with copious water and dried. It wassubsequently chromatographed on silica gel with ethyl acetate/hexane1:1. There was obtained 0.085 g (66%) of4-amino-N-(1H-indol-4-yl)-benzenesulfonamide as a white amorphous solid;m.p.: 215° C.

EXAMPLE 53

4-Amino-N-(2-methylamino-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamide

0.15 g (0.00076 mol) of 4-amino-2-chloro-6-trifluoromethylpyridine wasdissolved in 4 ml of pyridine, treated with 0.26 g (0.0015 mol) of4-acetamino-benzenesulfochloride and stirred at 60° C. for 20 hours.After removal of the solvent the residue was taken up in 10 ml of 1NHCl, extracted twice with 20 ml of ethyl acetate each time, the combinedorganic phases were washed with saturated sodium chloride solution anddried over sodium sulfate. Then, the mixture was freed from solvent andthe residue was dried in a high vacuum. There was obtained 0.20 g (67%)ofN-[4-(2-chloro-6-trifluoromethyl-pyridin-4-ylsulfamoyl)-phenyl]-acetamideas orange-yellow crystals; MS (ISP): me/e =394 (C₁₄ H₁₂ ClF₃ N₃ O₃ S⁺).

0.20 g (0.0005 mol) ofN-[4-(2-chloro-6-trifluoromethyl-pyridin-4-ylsulfamoyl)-phenyl]-acetamidewas dissolved in a mixture of 5 ml of 1N NaOH and 5 ml of dioxan andboiled at reflux for 5 hours. After cooling the dioxan was distilledoff, the residue was adjusted to pH 6 with 0.1N HCl, the aqueous phasewas extracted with ethyl acetate, back-washed with saturated sodiumchloride solution and the organic phase was dried over Na₂ SO₄.Subsequently, chromatography was carried out on silica gel with ethylacetate/hexane 1:4. There was obtained 0.06 g (34%) of4-amino-N-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamideas pale yellow crystals; m.p.: 179-181° C.

0.052 g (0.00015 mol) of4-amino-N-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamidewas stirred in 30 ml of 8M methylamine in ethanol in an autoclave at135° C. for 80 hours. The methylamine was allowed to evaporate, theresidue was dissolved in ethanol, treated with 2 g of silica gel,concentrated and the residue was chromatographed on silica gel withethyl acetate/hexane 1:2. There was obtained 0.036 g (70%) of4-amino-N-(2-methylamino-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamideas colorless crystals; m.p.: >68° C. (dec.).

EXAMPLE A

Tablets of the following composition are produced in the usual manner:

    ______________________________________                                                        mg/tablet                                                     ______________________________________                                        Active substance  100                                                         Powd. lactose     95                                                          White corn starch 35                                                          Polyvinylpyrrolidone                                                                             8                                                          Na carboxymethylstarch                                                                          10                                                          Magnesium stearate                                                                               2                                                          Tablet weight     250                                                         ______________________________________                                    

We claim:
 1. A compound of the formula ##STR21## wherein R² is hydrogenor lower alkyl;R^(7a) is amino or lower alkylamino; R^(8a) is amino,lower alkylamino, benzylamino, lower alkoxy, pyrrolidin-1-yl orazetidin-1-yl, with the proviso that when R^(8a) is lower alkoxy, thenR^(7a) is amino;or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1, whereinR² is hydrogen or methyl; R^(7a)is amino methylamino, ethylamino, propylamino, or isopropylamino; andR^(8a) is amino, methylamino, ethylamino, propylamino, isopropylamino,benzylamino, methoxy, pyrrolidin-1-yl or azetidin-1-yl.
 3. Apharmaceutical composition comprising a compound of the formula##STR22## wherein R² is hydrogen or lower alkyl;R^(7a) is amino or loweralkylamino; R^(8a) is amino, lower alkylamino, benzylamino, loweralkoxy, pyrrolidin-1-yl or azetidin-1-yl, with the proviso that whenR^(8a) is lower alkoxy, then R^(7a) is amino;or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically inert carrier material.4. A pharmaceutical composition according to claim 3, whereinR² ishydrogen or methyl; R^(7a) is amino, methylamino, ethylamino,propylamino, or ispropylamino; and R^(8a) is amino, methylamino,ethylamino, propylamino, isopropylamino, benzylamino, methoxy,pyrrolidin-1-yl or azetidin-1-yl.
 5. A compound of the formula ##STR23##wherein R² is hydrogen or lower alkyl;R^(7a) is amino, lower alkylamino,mercapto, pyrrolidin-1-yl or azetidin-1-yl; R^(8a) is amino or loweralkylamino, with the proviso that when R^(7a) is pyrrolidin-1-yl, thenR^(8a) is amino, or a pharmaceutically acceptable salt thereof.
 6. Acompound according to claim 5, whereinR² is hydrogen or methyl; R^(7a)is amino, methylamino, ethylamino, propylamino, ispropylamino, mercapto,pyrrolidin-1-yl or azetidin-1-yl; and R^(8a) is amino, methylamino,ethylamino, propylamino, or isopropylamino.
 7. A pharmaceuticalcomposition comprising a compound of the formula ##STR24## wherein R² ishydrogen or lower alkyl;R^(7a) is amino, lower alkylamino, mercapto,pyrrolidin-1-yl or azetidin-1-yl; R^(8a) is amino or lower alkylamino,with the proviso that when R^(7a) is pyrrolidin-1-yl, then R^(8a) isamino,or a pharmaceutically acceptable salt thereof, and apharmaceutically inert carrier material.
 8. A pharmaceutical compositionaccording to claim 7, whereinR² is hydrogen or methyl; R^(7a) is amino,methylamino, ethylamino, propylamino, ispropylamino, mercapto,pyrrolidin-1-yl or azetidin-1-yl; and R^(8a) is amino or methylamino,ethylamino, propylamino, isopropylamino.
 9. A compound according toclaim 1, wherein R^(7a) is amino and R^(8a) is methylamino.
 10. Acompound according to claim 1, wherein R^(7a) is amino and R^(8a) isethylamino.
 11. A compound according to claim 1, wherein R^(7a) is aminoand R^(8a) is benzylamino.
 12. A compound according to claim 1, whereinR^(7a) is methylamino and R^(8a) is methylamino.
 13. A compoundaccording to claim 1, wherein R^(7a) is methylamino and R^(8a) isethylamino.
 14. A compound according to claim 1, wherein R^(7a) ismethylamino and R^(8a) is isopropylamino.
 15. A compound according toclaim 1, wherein R^(7a) is methylamino and R^(8a) is azetidin-1-yl. 16.A compound according to claim 1, wherein R^(7a) is methylamino andR^(8a) is pyrrolidin-1-yl.
 17. A compound according to claim 1, whereinR^(7a) is ethylamino and R^(8a) is methylamino.
 18. A compound accordingto claim 1, wherein R^(7a) is ethylamino and R^(8a) is ethylamino.
 19. Acompound according to claim 1, wherein R^(7a) is ethylamino and R^(8a)is isopropylamino.
 20. A compound according to claim 1, wherein R^(7a)is ethylamino and R^(8a) is azetidin-1-yl.
 21. A compound according toclaim 1, wherein R^(7a) is propylamino and R^(8a) is propylamino.
 22. Acompound according to claim 1, wherein R^(7a) is isopropylamino andR^(8a) is ethylamino.
 23. A compound according to claim 1, whereinR^(7a) is amino and R^(8a) is methoxy.
 24. A compound according to claim1, wherein R² is methyl and R^(7a) is methylamino and R^(8a) ismethylamino.
 25. A compound of the formula ##STR25## wherein R^(1c) ishydrogen, 4-halo, 4-lower alkyl, 3-halo or 3-trifluoromethyl; andR¹⁵ islower alkyl,or a pharmaceutically acceptable salt thereof.
 26. Acompound according to claim 25, wherein R^(1c) is hydrogen, 4-fluoro,4-chloro, 4-methyl, 4-tert.butyl, 3-chloro or 3-trifluoromethyl and R¹⁵is methyl.
 27. A compound according to claim 26, wherein R^(1c) is4-chloro and R¹⁵ is methyl.
 28. A compound according to claim 26,wherein R^(1c) is t-butyl and R¹⁵ is methyl.
 29. A compound according toclaim 26, wherein R^(1c) is 4-fluoro and R¹⁵ is methyl.
 30. A compoundaccording to claim 26, wherein R^(1c) is hydrogen and R¹⁵ is methyl. 31.A compound according to claim 26, wherein R^(1c) is 4-methyl and R¹⁵ ismethyl.
 32. A compound according to claim 26, wherein R^(1c) is 3-chloroand R¹⁵ is methyl.
 33. A compound according to claim 26, wherein R^(1c)is 3-trifluoromethyl and R¹⁵ is methyl.
 34. A compound of the formula##STR26## wherein R^(9a) and R^(10a) are lower alkylamino,or apharmaceutically acceptable salt thereof.
 35. A compound according toclaim 34, wherein R^(9a) and R^(10a) are each methylamino.
 36. Acompound of the formula ##STR27## wherein R^(1d) is 3-lower alkyl,4-lower alkyl, 3-halo or 4-halo; andR^(9a) and R^(10a) are loweralkylamino,or a pharmaceutically acceptable salt thereof.
 37. Apharmaceutical composition according to claim 3, wherein R² is hydrogen,R^(7a) is methylamino and R^(8a) is methylamino.
 38. A pharmaceuticalcomposition according to claim 3, wherein R² is hydrogen, R^(7a) ismethylamino and R^(8a) is ethylamino.
 39. A pharmaceutical compositionaccording to claim 3, wherein R² is hydrogen, R^(7a) is ethylamino andR^(8a) is ethylamino.
 40. A pharmaceutical composition according toclaim 3, wherein R² is methyl, R^(7a) is methylamino and R^(8a) ismethylamino.
 41. A pharmaceutical composition comprising a compound ofthe formula ##STR28## wherein R^(1c) is hydrogen, 4-halo, 4-lower alkyl,3-halo or 3-trifluoromethyl; andR¹⁵ is lower alkyl,or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically inert carrier material.42. A pharmaceutical composition according to claim 41, wherein R^(1c)is hydrogen, 4-fluoro, 4-chloro, 4-methyl, 4-tert.butyl, 3-chloro or3-trifluoromethyl and R¹⁵ is methyl.
 43. A pharmaceutical compositionaccording to claim 42, wherein R^(1c) is 3-chloro and R¹⁵ is methyl. 44.A pharmaceutical composition according to claim 42, wherein R^(1c) is3-trifluoromethyl and R¹⁵ is methyl.
 45. A pharmaceutical compositioncomprising a compound of the formula ##STR29## wherein R^(9a) andR^(10a) are lower alkylamino,or a pharmaceutically acceptable saltthereof, and a pharmaceutically inert carrier material.
 46. Apharmaceutical composition comprising a compound of the formula##STR30## wherein R^(1d) is 3-lower alkyl, 4-lower alkyl, 3-halo or4-halo; andR^(9a) and R^(10a) are lower alkylamino,or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically inert carrier material.47. A compound according to claim 5, wherein R² is hydrogen.
 48. Acompound according to claim 5, wherein R^(7a) is azetidin-1-yl andR^(8a) is methylamino.
 49. A compound according to claim 5, whereinR^(7a) is azetidin-1-yl and R^(8a) is ethylamino.
 50. A compoundaccording to claim 5, wherein R^(7a) is mercapto and R^(8a) is amino.51. A pharmaceutical composition according to claim 7, wherein R² ishydrogen, R^(7a) is azetidin-1-yl and R^(8a) is methylamino.
 52. Apharmaceutical composition according to claim 7, wherein R² is hydrogen,R^(7a) is azetidin-1-yl and R^(8a) is ethylamino.
 53. A compoundaccording to claim 1, wherein R² is hydrogen.